s. sjogrens

Sjögren’s Syndrome

2009

History and Definition

Incidence and Etiology

Clinical findings

Diagnosis and Pathology

Prognosis and Treatment

Outline

HistoryMikulicz - first description of Sjögren’s syndrome

Mikulicz’s syndrome-1892 described parotid and lacrimal gland enlargement associated with a small round cell infiltrate .

However, the term Mikulicz's syndrome could encompass so many different entities including tuberculosis, other infections, sarcoidosis, and lymphoma. Therefore not given credit for discovery.

The term is still occasionally used to describe the histological appearance of focal lymphocytic infiltrates on salivary gland biopsies.

HistoryHenrick Sjögren 1899-1987 Sweden1930-As ophthalmology resident discover women with rheumatism and corneal abrasions who could not produce tears when crying and could not dissolve a lump of sugar in their mouths. 1933-Published his thesis paper on Keratoconjuctivitis Sicca, describing 15 women with lacrimal gland dysfunction leading to ulcerative lesions of the eyes. Was not well received, did not acquire Docenti (Academic PhD).1951-Sjögren published a series of papers describing 80 patients with the syndrome, in which the majority had arthritis. Sjögren’s syndrome was then recognized in literature.

Definition

Sjögren’s (show-grin) syndrome - a syndrome describing xerophthalmia (dry eyes) and xerostomia (dry mouth)- (Sicca complex)-due to immune-mediated destruction of exocrine glands, predominately of lacrimal and salivary.

Definition

Primary Sjögren’s syndrome - characterized by Sicca complex and extra-glandular symptoms without any additional connective tissue disorder.

Secondary Sjögren’s syndrome occurs in association with another autoimmune disorder such as SLE, RA, or scleroderma

IncidenceAs many as 1-2 million people in

the US are affected,

Prevalence of 1-3% of the population

It is in the top three of rheumatic diseases behind

systemic lupus erythematosis and rheumatoid arthritis

Approximately 30% of RA pt have SS.

Primary Sjögren’s Syndrome has a

ratio 9:1 of women to men

Age range from 40-60, with mean of

52.7 years.However, case

reports have been seen in children.

Pathogenesis of Sjögren’s syndrome is believed to be multifactorial.

Known to be autoimmune, but studies suggest that the disease process has genetic, environmental and neuroendocrine components

Etiology

EtiologyThere is a genetic predominance of HLA-DR genotype in SS patients. HLA-DR is a major histocompatibility complex, MHC class II cell surface receptor. It is found on antigen presenting cells.

These genotypes may also produce dysfunctional glands that secrete abnormal amounts of immune-stimulatory chemokines. This is not seen in patients without Sjögren’s disease.

EtiologyAutoimmunity involved in Sjögren’s disease is still poorly understood. It is believed that genetically defective glandular tissue combined with immunologic, environmental or neuroendocrine factors leads to loss of self antigen awareness.

Environmental factors may have link to viruses (Epstein–Barr virus, hepatitis C virus, human T-cell leukemia virus-1)

After the initial trigger, this glandular tissue autoimmune complex then becomes infiltrated with lymphocytes, predominately CD4 T cell (attracted by MHC class II)

A cascade of events then occur with the CD4 T cell release of cytokine IL-1, TNF, and interferon-gamma, which have destructive effects on the tissue and interfere with acetylcholine release, causing dysfunctional glands.

Clinical Manifestations

Glandular

Ocular

Oral

Otological

Laryngeal

Thyroid

Pulmonary

Sinus/nasal

Hepatobiliary and gastrointestinal

Genitourinary

Musculoskeletal

Vascular

Neurologic

Hematologic/lymphatic

Glandular manifestations

Decreased lacrimal flow

Corneal and conjunctiva epithelia damage

Leads to dry eyes, foreign body sensation, irritation, photosensitivity, thick secretions at inner canthus, and visual impairment.

Sjögren’s syndromedry eye

Glandular manifestations

Involvement of unilateral or bilateral major and minor salivary glands

Decreased salivary secretions-loss of lubrication, buffering and antimicrobial capacities of saliva.

Most common complication is increase in dental caries, especial root and incisor caries.

Frequent fungal infections

Tongue fissures

Persistent salivary enlargement.

Tooth decay due to xerostomia

Acute pseudomembranous candidiasis

Parotid Enlargementoccurs in 1/3 of SS patients


SS patients typically demonstrate mild to moderate sensorineural hearing loss in high frequencies.

An association with anti-cardiolipin antibodies has been demonstrated, but no cochlear or vestibular pathology has been found.

May be caused by immune complexes in the stria vascularis of the basal turn of the cochlea.


Granulomatous and non-granulomatous laryngeal nodes have been described.

Bamboo nodes - whitish or yellowish transverse submucosal lesions localized to middle third of vocal fold.

However, hoarseness is rare first symptom

Bamboo nodes


thyroid abnormalities such as Hashimotos’s thyroiditis are associated with SS

Antibodies to thyroglobulin can be found in up to 1/2 of SS patients

10-15% of Primary SS are clinically hypothyroid

Therefore, all patients with SS should undergo routine evaluation of thyroid function


Epistaxis and nasal crusting are common findings in SS, with 50% having nasal mucosa hypertrophy and up to 13% have septal perforations

Xerotrachea (dry cough) and dyspnea are common pulmonary symptoms.

Esophageal spasm and dysmotility are also seen, but may be secondary to absence of saliva

Atrophic gastritis, celiac disease


Lymphoma is a serious complication of SS, occurring late in the disease.

Risk of lymphoma is 44 times greater than the general population.

Lymphomas are classified as marginal-zone B-cell lymphomas, caused by chronic stimulation of auto-reactive B cells.

Diffuse large B-cell lymphoma in a 30 year-old woman with Sjögren’s

syndrome.


20-30% of patients have vasculitis, which includes palpable purpura, petechiae, or subcutaneous nodules

Renal involvement in 10% of patients-interstitial nephritis.

Renal tubular acidosis also seen which is secondary to hyper-gammaglobulinemia

Myalgias, arthralgias, fatigue, and malaise

A)Palpable purpura in the lower extremities.

B)Multiple necrotic cutaneous ulcers of the lower extremities in a patient with primary Sjögren's syndrome

C)Annular urticarial lesions of the trunk

Criteria for Sjögren’s syndrome 2002

US and European diagnosis criteria differed so much that there were ten times as many diagnosis in Europe than in US.

Caused problems with clinical trials and publication reports

2002 American-European Consensus Group developed criteria for Sjögren syndrome.

Criteria for Sjögren’s syndrome 2002

Ocular symptoms

Oral symptoms

Objective evidence of dry eyes

Objective evidence of salivary-gland involvement

Laboratory abnormality

Criteria for Sjögren’s syndrome 1. Ocular Symptoms (at least one must be present)Persistent dry eyes every day for more than 3 monthsRecurrent sensation of sand or gravel in eyesUse of tear substitute more than three time a day

2. Oral symptoms (at least one present)Feeling of dry mouth every day for 3 monthsRecurrent swollen salivary glands as an adultNeed to drink liquids to aid in swallowing of dry foods.

xerostomia induced glossitis

Criteria for Sjögren’s syndrome3. Objective evidence of dry eyes (one must be present)Schirmer TestRose-Bengal

4. Lacrimal-gland biopsyFocal lymphocytic sialoadenitis in minor salivary glands-containing more than 50 lymphocytes per 4 mm of glandular tissue.

Schirmer’s testThis test consists of placing a small strip of filter paper inside the lower eyelid (conjunctiva sac). The eyes are closed for 5 minutes. The paper is then removed and the amount of moisture is measured. <5 mm in 5 minutes is positive for SS

Rose Bengal dyeRose Bengal (4,5,6,7-tetrachloro-2',4',5',7'-tetraiodofluorescein) is a stain. Its sodium salt is commonly used in eye drops to stain damaged conjunctiva and corneal cells and thereby identify damage to the eye.

Labial gland biopsyA gold standard of diagnosis

Histopathology of labial gland biopsy

Lymphocytic and plasma cells infiltrateTwo excretory ducts and 3 mucous

salivary gland acini are seen

Criteria for Sjögren’s syndrome5. Objective evidence of salivary gland involvement(one must be present)Salivary-gland scintigraphy

Parotid sialography

Unstimulated whole sialometry- < 1.5 ml in 15 min

Scintigraphy Must show delayed uptake of

technetium-99m

Criteria for Sjögren’s syndrome•6. Laboratory Abnormality (one must be present)•Anti-SS-A(Ro) or Anti SS-B(La)(more specific)

•ANA

•IgM rheumatoid factor

LaboratorySS patients of both primary and secondary Sjögren’s syndrome have marked hypergammaglobulinemia (IgG>IgA>IgM), elevated total protein and sedimentation rate, persistent rheumatoid factors, and a decreased WBC count.

SS-A/Ro and SS-B/La (anti-RNA antibodies). Antibodies occur in approximately 60% of patients with Sjögren's syndrome and are associated with early disease onset, longer disease duration, parotid gland enlargement, a higher frequency of extra-glandular manifestations, and more intense lymphocytic infiltration

These test are nonspecific, also seen in many autoimmune inflammatory conditions.

Indirect immunofluoresceinanti-SSA/Ro autoantibodies

Criteria for Sjögren’s syndrome Primary SS is

defined as the presence of 4 of the 6 diagnostic criteria present.

Secondary SS is defined as presence of connective tissue disease with a positive category 1 or 2 and a positive result in 2 of the remaining 4 criteria

Exclusion criteriaPast head and neck radiation treatment

Hep C infection

AIDS

Pre-existing lymphoma or sarcoidosis

Graft vs host disease

Anticholinergic drugs

Prognosis and Therapies

As with all autoimmune disease, there is no cure, and so therapy is aimed at symptomatic relief.

Sjögren’s syndrome is indolent in its course, but one must be aware of the risk of lymphomas in this patient population.

Mavragani CP et al. (2006) The management of Sjögren's syndromeNat Clin Pract Rheumatol 2: 252–261 doi:10.1038/ncprheum0165

Table 1 Management of glandular manifestations of primary Sjögren's syndrome

MedicationsOral anti-muscarinic therapy proven useful for xerostomia.

Pilocarpine-first muscarinic receptor antagonist approved by FDA for use in Sjögren syndrome. Dose 5mg qid.

Evoxac is next generation muscarinic receptor with greater affinity, but less cardiac side effects of anti-muscarinic therapy.

MedicationsExtra-glandular disease such as muscular pains, renal and pulmonary disease may benefit from use of immune modulator such as systemic steroids and anti-malarials.

However, these therapies have not been proven to provide help with sicca symptoms.

ConclusionSjögren’s syndrome has early ENT manifestations-that include dry mouth and parotid enlargement.

Otolaryngologist, as part of a multidisciplinary team, may prevent prolong delays in the disease by having a high degree of suspicion.

Otolaryngologist play key role in diagnostic evaluation, biopsy and treatment.

Sorry for the dry lecture, but this is

Sjögren’s syndrome.

Questions?

ReferencesRehman, Habab-ur Sjögren’s syndrome Yonsei medical journal vol. 44, No. 6, pp 947-954, 2003

Fox PC. Autoimmune diseases and Sjogren’s syndrome: an autoimmune exocrinopathy. Ann N Y Acad Sci 2007;1098:15–21

Mavragani CP, Moutsopoulos NM, Moutsopoulos HM. The management of Sjögren's syndrome. Nat Clin Pract Rheumatol. May 2006;2(5):252-61

Manoussakis MN, Moutsopoulos HM. Sjögren's syndrome. Otolaryngol Clin North Am 1999;32:843-60

Gutta R. McLain L. McGuff SH. Sjögren syndrome: a review for the maxillofacial surgeon. Oral Maxillofac Surg Clin North Am. 2008 Nov;20(4):567-75

Clinical Manifestations and Early Diagnosis of Sjögren Syndrome Stuart S. Kassan and Haralampos M. Moutsopoulos Arch Intern Med. 2004;164(12):1275-1284

Sjögren's disease. Elizabeth J Mahoney, Jeffrey H Spiegel Otolaryngol Clin North Am Aug 2003 (Vol. 36, Issue 4, Pages 733-45)

Mavragani CP, Moutsopoulos HM Conventional Therapy of Sjogren's Syndrome. [Journal Article]Clin Rev Allergy Immunol 2007 Jun; 32(3):284-91

Fox RI. Sjögren's syndrome. Lancet. Jul 23-29 2005;366(9482):321-31

Srinivasan S, Slomovic AR Sjogren’s disease Compr Ophthalmol Update. 2007 Jul-Aug;8(4):205-12

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